No abstract

Background: Regular binge drinking is associated with numerous adverse consequences yet the U.S. Food and Drug Administration (FDA) has approved only 4 medications for the treatment of alcohol use disorders (AUDs), and none have been specifically targeted for treating binge drinking. Here we assessed the effectiveness of the dopamine/norepinephrine reuptake inhibitor, bupropion (BUP), alone and in combination with naltrexone (NAL), to reduce binge-like and chronic ethanol intake in mice. While BUP is an FDA-approved drug that is currently used to treat depression and nicotine dependence there has been only limited investigation to assess the ability of BUP to reduce ethanol intake. Methods: Male C57BL/6J mice were tested with 20% (v/v) ethanol using "drinking in the dark" (DID) procedures to model binge-like ethanol intake and following intermittent access to ethanol (IAE). In Experiment 1, mice were given intraperitoneal (i.p.) injection of 0, 20, or 40 mg/kg BUP 30-min before DID testing, in Experiment 2 mice were given i.p. injection of vehicle, BUP (20 mg/kg), NAL (3 mg/kg), or BUP + NAL (20 and 3 mg/kg, respectively) 30 min before DID testing, and in Experiment 3 mice were given i.p. injection of 0, 20, 40 or 60 mg/kg BUP 30-min before ethanol access after mice had 16-weeks of IAE. Results: BUP dose-dependently blunted ethanol intake with DID procedures and after 16-weeks of IAE. Administration of subthreshold doses of BUP + NAL also reduced binge-like ethanol intake. Finally, BUP failed to reduce consumption of a 3% (w/v) sucrose solution.

The inbred high drinking in the dark (iHDID1 and iHDID2) strains are two replicate lines bred from the parent HS/Npt (HS) line for achieving binge levels of blood ethanol concentration (≥80 mg/dL BEC) in a four-hour period. In this work, we sought to evaluate differences in baseline and ethanol-induced c-Fos activation between the HS, iHDID1, and iHDID2 genetic lines in brain regions known to process the aversive properties of ethanol. Methods: Male and female HS, iHDID1, and iHDID2 mice underwent an IP saline 2 3 g/kg ethanol injection. Brain sections were then stained for c-Fos expression in the basolateral/central amygdala (BLA/CeA), bed nucleus of the stria terminals (BNST), A2, locus coeruleus (LC), parabrachial nucleus (PBN), lateral/medial habenula (LHb/MHb), paraventricular nucleus of the thalamus (PVT), periaqueductal gray (PAG), Edinger–Westphal nuclei (EW), and rostromedial tegmental nucleus (RMTg). Results: The iHDID1 and iHDID2 lines showed similar and distinct patterns of regional c-Fos; however, in no region did the two both significantly differ from the HS line together. Conclusions: Our findings lend further support to the hypothesis the iHDID1 and the iHDID2 lines arrive at a similar behavior phenotype through divergent genetic mechanisms.